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. 2022 Oct 26;85(11):2650–2655. doi: 10.1021/acs.jnatprod.2c00749

(±)-Polysiphenol and Other Analogues via Symmetrical Intermolecular Dimerizations: A Synthetic, Spectroscopic, Structural, and Computational Study

D Christopher Braddock 1,*, Anna Duran-Corbera 1, Masih Nilforoushan 1, Ziye Yang 1, Tianyou He 1, Gajan Santhakumar 1, Karim A Bahou 1, Henry S Rzepa 1, Rudiger Woscholski 1, Andrew J P White 1
PMCID: PMC9706781  PMID: 36288514

Abstract

graphic file with name np2c00749_0006.jpg

We report an improved total synthesis of 4,5-dibromo-9,10-dihydrophenanthrene-2,3,6,7-tetraol, (±)-polysiphenol, via intermolecular McMurray dimerization of 5-bromovanillin and subsequent intramolecular oxidative coupling as the key steps. The synthetic route is applicable to 4,5-dichloro- and 4,5-difluoro-halologues (as well as a 4,5-dialkyl-analogue). Distinctive AA′BB′ multiplets in their 1H NMR spectra for the dimethylene bridges of the dibromo and dichloro compounds reveal them to be room-temperature stable atropisomers, while for the difluoro compound they present as a singlet. X-ray crystal structure determinations of their tetramethylated synthetic precursors show atropisomeric twist angles of 48°, 46°, and 32°, respectively, with the former representing the largest yet observed in any 4,5-disubstituted-9,10-dihydrophenanthrene. DFT computational studies reveal an unprecedented two-stage atropisomeric interconversion process involving time-independent asynchronous rotations of the dimethylene bridge and the biaryl axis for halologues containing chlorine or bromine, but a more synchronous rotation for the difluoro analogue.

Marine red algae provide structurally diverse halogenated metabolites as stimulating structures for target synthesis and as prospective leads for medicinally potent entities.1 In 2011 we reported the first total synthesis of (±)-polysiphenol (1a),2 a compound isolated from Polysyphonia ferulacea, as an atropisomerically stable 4,5-dibrominated 9,10-dihydrophenanthrene and the first naturally occurring 9,10-dihydrophenanthrene from a marine source.3 Our original synthesis featured a one-pot telescoped bromination–phosphonium salt formation–Wittig reaction to join two nonidentical aromatic fragments, followed by a highly regioselective, biomimetically inspired, intramolecular oxidative coupling (Figure 1a). To date, this represents the only total synthesis as yet reported for (±)-polysiphenol, or related brominated metabolites with a phenanthrene skeleton.4 While some potent biological activity has been reported for these latter compounds, any biological activity of polysiphenol (1a) remains to be established. However, attempts to revisit our synthesis to provide further quantities of polysiphenol for such purposes revealed that the one-pot telescoped bromination–phosphonium salt formation–Wittig reaction could be capricious, returning the desired product in wildly varying yield (8–79%). Herein, in an effort to overcome these difficulties, and to take synthetic advantage of the inherent symmetry present in the target molecule, we report the direct McMurray dimerization of 5-bromovanillin as a more efficient approach to (±)-polysiphenol 1a (Figure 1b). We show that this synthetic route can be readily adapted to provide its chlorinated and fluorinated halologues as compounds for putative structure–activity relationship (SAR) studies. X-ray crystal structure determinations of their tetra-O-methylated precursors provide the first experimental information about the extent of their atropisomeric twist angles, and computational studies provide insight into their atropisomeric stability and interconversion pathways.

Figure 1.

Figure 1

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(a) Previous work. (b) This work.

Results and Discussion

In revisiting our synthetic approach to (±)-polysiphenol 1 we were aware that Harvey had recently reported the first direct McMurray dimerization of vanillin,5 by consideration and modification of previous work.6 Accordingly, we were drawn to investigate Harvey’s conditions for the direct McMurray dimerization of commercially available 5-bromovanillin 2a (Scheme 1). Much to our delight, this procedure provided stilbene 3a(7) in pure form directly after workup. Subsequent hydrogenation provided novel 4,4′-diphenol-1,2-ethane 4a, which after dimethylation intersected with our previous route as intermediate 5a.2 This three-step conversion of 2a to 5a requires no chromatographic purification and compares favorably to the previous four-step route by removing the capricious bromination–phosphonium salt formation–Wittig reaction step.2 Subsequent regioselective oxidative coupling to form the dibromodihydrophenanthrene 6a and global demethylation both as previously reported2 provided (±)-polysiphenol 1a.

Scheme 1. Synthesis of 4,5-Disubstituted-9,10-dihydrophenanthrene-2,3,6,7-tetraols 1a–1d.

Scheme 1

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The same synthetic sequence provided the 4,5-dichloro- and 4,5-difluoro-9,10-dihydrophenanthrene halologues 1b and 1c starting from commercially available 5-chloro- and 5-fluorovanillin 2b and 2c without significant complications (Scheme 1). In the case of the fluorine halologue, the oxidative coupling step (5c → 6c) gave also overoxidized 4,5-difluorophenanthrene 7c, which had not been observed in the oxidative couplings of dibromo (5a → 6a) or dichloro (5b → 6b) analogues.8 We attribute this different behavior to the ability of the smaller fluorine atoms to be more readily accommodated within the planar structure of a phenanthrene.9 This observation was also the first indication of the lack of atropisomeric stability in difluoride 6c (and 1c) (vide infra). It was found that difluorophenanthrene 7c could be smoothly reduced back to dihydrophenanthrene 6c using Pd/C and hydrogen gas in quantitative yield.

4,5-Dialkyl analogue 1d was also produced starting from known 5-allyl vanillin 2d (Scheme 1), the latter being readily obtained via aromatic Claisen rearrangement of O-allyl vanillin.10 This sequence also proceeded without complication, where the unsaturated allyl groups are transformed into n-propyl groups in the hydrogenation step (3d → 4d), albeit with a subsequent difficult O-alkylation step (4d → 5d), which did not improve regardless of the conditions employed (which we attribute to the amphiphilic nature of the substrate).

As previously reported, the atropisomeric axis in polysiphenol 1a gives rise to a distinctive AA′BB′ multiplet for the dimethylene bridge protons in its 1H NMR spectrum at room temperature.3 A similar pattern is also observed for dichloride 1b and dipropyl 1d prepared here, indicative of stable atropisomers also. In contrast, the methylene bridge for the difluoride 1c presents as a singlet, indicating that the smaller fluorine atoms do not result in restricted rotation at this temperature.11 The 1H NMR spectra of tetramethyl precursors 6a–6d show the same features, respectively. Pleasingly, we were able to obtain X-ray crystal structures for all four of these compounds for comparison (Figure 2 and Supporting Information).

Figure 2.

Figure 2

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Top: X-ray crystal structure of dibromide 6a. Bottom: Definition of the structural parameters for 4,5-dihalo/dialkyl-2,3,6,7-tetramethoxy-9,10-dihydrophenanthrenes (6a–6d).

Inspection of the crystal structure for 4,5-dibromo-9,10-dihydrophenanthrene 6a (Figure 2, top) reveals an atropisomeric C2-symmetic twisted tricyclic core, as to be expected based on the above 1H NMR analysis and previous molecular mechanics modeling for polysiphenol.3,12 This is the first crystal structure of any 4,5-dibromo-9,10-dihydrophenanthrene,13 revealing an internuclear Br–Br distance of d = 3.43 Å, torsion angles for α = 47.8° and β = 37.3°, and a dimethylene bridge with minimal torsional strain (γ = 60.1°). The α-torsion twist angle is the largest yet to be observed in any 4,5-disubstituted-9,10-dihydrophenanthrene. Dipropyl derivative 6d was found to have a smaller internuclear (benzylic methylene) C–C distance of 3.21 Å, but the torsion angles of 46.4° (α), 36.1° (β), and 61.0° (γ) reveal the dihydrophenanthrene unit to be essentially isostructural with dibromide 6a.

For dichloride 6b and difluoride 6c, unsurprisingly, the internuclear distances between the two halogens decrease with the decreasing size of the halogen (6b, Cl–Cl, d = 3.17 Å; 6c, F–F, d = 2.48 Å), and the observed α and β torsion angles decrease also (6b, α = 45.9°, β = 35.6°; 6c, α = 31.5°, β = 25.4°), in line with previous observations.14 In both cases the dimethylene bridges retain essentially perfect γ torsion angles (6b, 62.1°; 6c, 58.8°), presumably to minimize torsional strain, regardless of the variation in the other torsion angles. While the trend in X-ray structural parameters in the series 6a to 6b to 6c is clearly consistent with the 1H NMR data, which suggest a switch over from atropisomerically stable (6a, 6b)15 to non-atropisomerically stable (6c) structures at room temperature, we elected to undertake a computational study to assess the relative atropisomeric stability of 4,5-dihalo-9,10-dihydrophenanthrenes 6a–6c.

A ωB97XD/6-31G(d,p) density functional procedure16 with a CHCl3 solvent field applied17 was deemed sufficiently accurate to explore the atropisomeric potential energy surfaces for 1. The following combinations of halogens were used: Br, Br (1a), Cl,Br, Cl,Cl (1b), F,Cl, F,F (1c). Approximate transition states were initially located using relaxed scans and optimized accurately, and an intrinsic reaction coordinate (IRC)18 was obtained. That for dibromide 1a is shown in Figure 3 and reveals a two-stage, albeit concerted, process in which the transition state (IRC = 0.0) involves rotation of predominantly the biaryl C–C bond—whereby the two halogens pass each other—which is then followed (IRC = 8) by rotation of the methylene–methylene bond—overall transforming γ from ca. 60° to ca. −60°—with a lower effective barrier (∼15 kcal/mol) (see ref (20) for links to animations). The calculated atropisomeric barriers reduce in height as the halogens become smaller, ΔG⧧ 30.5 (Br,Br, 1a), 27.9 [23.4] (Me,Me), 27.5 (Br,Cl), 25.3 [22.6] (Cl,Cl, 1b), 14.7 (Cl,F), and 10.5 [11.1] (F,F 1c) kcal/mol, and show reasonable agreement with experimentally measured values19 (in square brackets). At ambient temperatures therefore, the combinations involving bromine, chlorine, and methyl will show no NMR exchange effects due to atropisomerism, while the low F,F barrier would result in fully averaged NMR behavior, as seen experimentally. The combination Cl,F is predicted to show intermediate NMR behavior.

Figure 3.

Figure 3

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Computed relative energies as a function of intrinsic reaction coordinate for atropisomerism of dibromide 6a, with diaryl rotations followed by methylene rotations.

As the halogen size decreases, the nature of the two-stage atropisomeric process evolves from one in which the transition state corresponds to predominant halogen atropisomerism at the diaryl bond to one where it more closely resembles methylene rotation, the latter achieved only when both halogens are fluorine (Figure 4).

Figure 4.

Figure 4

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Computed relative energies as a function of intrinsic reaction coordinate for atropisomerism of difluoride 6c, with dimethylene rotations followed by diaryl rotations.

In conclusion, we have developed a total synthesis of (±)-polysiphenol 1a and its chlorinated and fluorinated halologues, 1b and 1c, respectively, as well as dialkyl analogue 1d via intermolecular McMurray dimerization and subsequent intramolecular oxidative coupling as the key steps. A combined spectroscopic, crystallographic, and computational study has shown that the dibromide 1a, dichloride 1b, and dialkyl 1d derivatives are atropisomerically stable at room temperature, but where the difluoride 1c is not20 and where the mixed fluoro/chloro halide is predicted to show intermediate behavior.

Experimental Section

General Experimental Procedures

See Supporting Information.

(E)-4,4′-(Ethene-1,2-diyl)bis(2-bromo-6-methoxyphenol) (3a)

TiCl4 (1.89 mL, 17.2 mmol, 2.0 equiv) was added dropwise to a stirred suspension of Mg (420 mg, 17.2 mmol, 2.0 equiv) in THF (100 mL) at −78 °C. The mixture was allowed to warm to rt and became black. After stirring for 1 h, a solution of bromovanillin 2a (2.00 g, 8.6 mmol) in THF (20 mL) was added dropwise and was stirred overnight. The solvent was removed in vacuo, and the black solid mass was treated with 2 M aqueous HCl (200 mL). The resulting suspended solids were collected by vacuum filtration, washed successively with H2O and n-hexane, and dried under vacuum to yield dibromostilbene 3a (1.20 g, 2.79 mmol, 65%) as an off-white solid: IR (neat) 3433 (br) cm–1; 1H NMR (400 MHz; DMSO-d6) δ 9.55 (s, 2H), 7.27 (d, J = 1.8 Hz, 2H), 7.19 (d, J = 1.8 Hz, 2H), 7.04 (s, 2H), 3.88 (s, 6H) ppm; 13C NMR (100 MHz; DMSO-d6) δ 148.6, 143.3, 129.8, 125.9, 122.7, 109.6, 108.5, 56.2 ppm; HRMS (ES–, TOF) m/z: 426.9196 [M – H]− (calcd for C16H1379Br2O4, 426.9181).

4,4′-(Ethane-1,2-diyl)bis(2-bromo-6-methoxyphenol) (4a)

Pd/C (10 wt %, 320 mg) was added to a solution of stilbene 3a (1.20 g, 2.79 mmol) in THF (80 mL) at rt, and the resulting suspension was stirred vigorously under an atmosphere of hydrogen gas. After 24 h, the mixture was filtered and evaporated to give dibromoethane 4a (1.20 g, 2.54 mmol, 98%) as a pale pink solid: IR (neat) 3376 (br), 2956, 2927, 2864 cm–1; 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 2H), 6.94 (d, J = 1.8 Hz, 2H), 6.83 (d, J = 1.8 Hz, 2H), 3.78 (s, 6H), 2.72 (s, 4H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 148.2, 141.7, 133.6, 123.8, 111.6, 109.0, 56.1, 36.5 ppm.

1,2-Bis(3-bromo-4,5-dimethoxyphenyl)ethane (5a)

To a stirred solution of bis(methoxyphenol) 4a (1.0 g, 2.3 mmol) in dimethylformamide (DMF) (25 mL) at rt was added potassium carbonate (950 mg, 6.9 mmol, 3.0 equiv). After 10 min, methyl iodide (0.29 mL, 4.6 mmol, 2.0 equiv) was added, the mixture was stirred overnight at 50 °C, the solvent was evaporated, and H2O was added. The aqueous phase was extracted with diethyl ether (3 × 200 mL), and the combined organics were washed with saturated aqueous sodium carbonate solution (200 mL) and brine (200 mL), dried over sodium sulfate, and evaporated to yield the dibromotetramethyl ether 5a (1.02 g, 96%) as a white crystalline solid: mp 105–108 °C (lit.2 102 °C); IR (neat) 3002, 2965, 2933 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J = 1.8 Hz, 2H), 6.57 (d, J = 1.8 Hz), 3.83 (s, 6H), 3.81 (s, 6H), 2.80 (s, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ 153.6, 144.9, 138.5, 124.5, 117.5, 112.3, 60.7, 56.2, 37.5 ppm.

(E)-4,4′-(Ethene-1,2-diyl)bis(2-chloro-6-methoxyphenol) (3b)

According to the procedure for stilbene 3a, using 5-chlorovanillin 2b (1.00 g, 5.35 mmol, 1.0 equiv), Mg (261 mg, 10.7 mmol, 2.0 equiv), and TiCl4 (1.18 mL, 10.7 mmol, 2.0 equiv) in THF gave dichlorostilbene 3b (677 mg, 1.98 mmol, 74%) as a pink crystalline solid: mp 231–237 °C; IR (neat) 3467 (br) cm–1; 1H NMR (400 MHz; DMSO-d6) δ 9.50 (s, 2H), 7.16–7.14 (m, 4H), 7.06 (s, 2H), 3.88 (s, 6H) ppm; 13C NMR (100 MHz; DMSO-d6) δ 148.9, 142.2, 129.1, 126.1, 120.4, 119.8, 108.0, 56.2 ppm; HRMS (APCI, Orbitrap) m/z 339.0183 [M – H]− (calcd for C16H1335Cl2O4, 339.0185).

4,4′-(Ethane-1,2-diyl)bis(2-chloro-6-methoxyphenol) (4b)

According to the procedure for diarylethane 4a, using stilbene 3b (500 mg, 1.47 mmol, 1.0 equiv) and Pd/C (10 wt %, 344 mg) in THF (45 mL) gave dichloroethane 4b (448 mg, 1.31 mmol, 89%) as a dark gray solid: IR (neat) 3396 (br), 2929 cm–1; 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 2H), 6.79 (s, 4H), 3.78 (s, 6H), 2.73 (s, 4H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 148.5, 140.7, 132.8, 121.0, 119.4, 111.1, 56.1, 36.5 ppm; HRMS (ES–, TOF) m/z 341.0353 [M – H]− (calcd for C16H1535Cl2O4, 341.0347).

1,2-Bis(3-chloro-4,5-dimethoxyphenyl)ethane (5b)

According to the procedure for tetramethyl ether 5a, using bis(methoxyphenol) 4b (385 mg, 1.12 mmol, 1.0 equiv), potassium carbonate (645 mg, 4.77 mmol, 4.3 equiv), and methyl iodide (0.70 mL, 12.5 mmol, 11.2 equiv) in DMF (13 mL) for 5 days at rt gave dichlorotetramethyl ether 5b (301 mg, 0.81 mmol, 72%) as a yellow solid: IR (neat) 2968, 2928, 2860, 2830, cm–1; 1H NMR (400 MHz, CDCl3) δ 6.80 (d, J = 2.2 Hz, 2H), 6.54 (d, J = 2.2 Hz, 2H), 3.84 (s, 6H), 3.82 (s, 6H), 2.81 (s, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ (ppm) 153.7, 143.9, 137.9, 128.2, 121.8, 111.6, 60.8, 56.2, 37.5 ppm; HRMS (ES+, TOF) m/z: 403.1087 [M + MeOH + H]+ (calcd for C19H2535Cl2O5, 403.1079).

4,5-Dichloro-2,3,6,7-tetramethoxy-9,10-dihydrophenanthrene (6b)

To a stirred solution of diarylethane 5b (160 mg, 0.43 mmol, 1.0 equiv) in CH2Cl2 (12 mL) at −78 °C were added [bis(trifluoroacetoxy)iodo]benzene (224 mg, 0.52 mmol, 1.2 equiv) and BF3·OEt2 (0.14 mL, 1.10 mmol, 2.5 equiv). The solution was allowed to warm to rt and stirred for 28 h. The mixture was filtered through a silica plug, and the volatiles were evaporated and recrystallization first from EtOAc and n-hexane and then from CH2Cl2 to give dichlorodihydrophenanthrene 6b (44 mg, 0.1 mmol, 28%) as colorless blocky needles: mp 161–165 °C; IR (neat) 3001, 2941, 2836 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.78 (s, 2H), 3.91 (s, 6H), 3.90 (s, 6H), 2.72–2.54 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ 152.4, 144.9, 137.5, 128.2, 125.8, 109.8, 60.9, 56.3, 31.5 ppm; HRMS (ES+, TOF) m/z 333.0906 [M – Cl]+ (calcd for C18H1835ClO4, 333.0894).

4,5-Dichloro-9,10-dihydrophenanthrene-2,3,6,7-tetraol (1b)

A solution of BBr3 in CH2Cl2 (1M, 0.37 mL, 0.37 mmol, 5.8 equiv) was added dropwise to tetramethyl ether 6b (24 mg, 0.06 mmol) in CH2Cl2 (1.7 mL) at −78 °C. The reaction mixture was allowed to warm to rt and stirred for 24 h, and the volatiles were evaporated to afford dichlorotetrol 1b (20 mg, 0.06 mmol, 98%) as a black solid: IR (neat) 3286 (br), 2939, 2855 cm–1; 1H NMR (400 MHz, CD3OD) δ 8.46 (s, 4H), 6.67 (s, 2H), 2.58–2.37 (m, 4H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 144.8, 140.7, 132.3, 123.7 120.1, 112.6, 30.5 ppm; HRMS (ES–, TOF) m/z 310.9883 [M – H]− (calcd for C14H935Cl2O4, 310.9878).

(E)-4,4′-(Ethene-1,2-diyl)bis(2-fluoro-6-methoxyphenol) (3c)

According to the procedure for stilbene 3a, using 5-fluorovanillin 2c (0.20 g, 1.17 mmol, 1.0 equiv), Mg (60 mg, 2.47 mmol), and TiCl4 (0.32 mL, 2.94 mmol) in THF gave difluorostilbene 3c (129 mg, 0.42 mmol, 72%) as an orange solid: IR (neat) 3460 (br) cm–1; 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 2H), 7.03–6.97 (m, 6H), 3.86 (s, 6H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 151.6 (d, J = 236 Hz), 149.6 (d, J = 7 Hz), 133.9 (d, J = 15 Hz), 128.1 (d, J = 9 Hz), 126.5, 106.4 (d, J = 20 Hz), 105.7, 56.1 ppm; 19F{1H} NMR (376 MHz, DMSO-d6) −135.8 ppm; HRMS (ES–, TOF) m/z 307.0777 [M – H]− (calcd for C16H13F2O4, 307.0782).

4,4′-(Ethane-1,2-diyl)bis(2-fluoro-6-methoxyphenol) (4c)

According to the procedure for diarylethane 4a, using stilbene 3c (188 mg, 0.61 mmol, 1.0 equiv) and Pd/C (10 wt %, 163 mg) in THF (17.5 mL) gave difluoroethane 4c (148 mg, 0.48 mmol, 78%) as a white solid: IR (neat) 3332 (br) cm–1; 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 2H), 6.65–6.61 (m, 4H), 3.76 (s, 6H) 2.73 (s, 4H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 151.2 (d, J = 235 Hz), 149.3 (d, J = 9 Hz), 132.1 (d, J = 14 Hz), 132.0, 108.1, 108.0, 56.1, 36.5 ppm; 19F{1H} NMR (376 MHz, DMSO-d6) −136.2 ppm; HRMS (ES–, TOF) m/z: 309.0925 [M – H]− (calcd for C16H15F2O4, 309.0938).

1,2-Bis(3-fluoro-4,5-dimethoxyphenyl)ethane (5c)

Methyl iodide (0.13 mL, 2.1 mmol, 10 equiv) was added to a stirred solution of potassium hydroxide (0.047 g, 0.84 mmol, 4 equiv) and bis(methoxyphenol) 4c (65 mg, 0.21 mmol) in DMSO (2 mL) and stirred overnight at rt. Water was added, the mixture was extracted with diethyl ether (4 × 10 mL), and the combined organics were washed successively with H2O (3 × 10 mL), saturated aqueous sodium carbonate solution (2 × 10 mL), and brine (10 mL). The resulting organic layer was dried over magnesium sulfate, evaporated, and chromatographed (EtOAc:PE 2:3) to give difluorotetramethyl ether 5c (59 mg, 0.17 mmol, 83%) as a white solid: IR 2930, 2836 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.57 (dd, J = 11.2, 1.9 Hz, 2H), 6.43 (t, J = 1.6 Hz, 2H), 3.90 (s, 6H), 3.82 (s, 6H, OMe), 2.81 (s, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ 156.0 (d, J = 244 Hz), 153.5 (d, J = 6 Hz), 137.0 (d, J = 8 Hz), 135.4 (d, J = 13 Hz), 108.9 (d, J = 19 Hz), 108.2, 61.7, 56.4, 37.6 ppm; 19F{1H} NMR (376 MHz, CDCl3) δ (ppm) −131.2; HRMS (CI+, Orbitrap) m/z 339.1402 [M + H]+ (calcd for C18H21F2O4, 339.1402).

4,5-Difluoro-2,3,6,7-tetramethoxy-9,10-dihydrophenanthrene (6c) and 4,5-difluoro-2,3,6,7-tetramethoxyphenanthrene (7c)

According to the procedure for dihydrophenathrene 6b, using diarylethane 5c (45 mg, 0.13 mmol), with [bis(trifluoroacetoxy)iodo]benzene (858 mg, 0.20 mmol, 1.5 equiv) and BF3·OEt2 (0.05 mL, 0.4 mmol, 3 equiv) in CH2Cl2 (12 mL), followed by chromatography (CH2Cl2:PE 2:1) gave first difluorophenanthrene 7c (0.012 g, 0.036 mmol, 27%) as a white solid: Rf 0.38 (CH2Cl2:PE 2:1); 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 2H), 7.05 (s, 2H), 4.07 (s, 6H), 4.02 (s, 6H) ppm; 19F{1H} NMR (376 MHz, CDCl3) δ −120.7 ppm; HRMS (CI+, Orbitrap) m/z 335.1077 [M + H]+ (calcd for C18H17F2O4, 335.1089), and second difluorodihydrophenanthrene 6c (16 mg, 0.048 mmol, 36%) as a white solid: Rf 0.31 (CH2Cl2:PE 2:1); mp 172–174 °C; IR 2930 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.63 (s, 2H), 3.94 (s, 6H), 3.90 (s, 6H), 2.68 (s, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ 153.4 (AA′XX′ sextet, JFF′ = 138.3 Hz, JFC = 188.2 Hz, JFC′ = 61.9 Hz), 152.4, 136.4 (t, J = 8 Hz), 134.4, 112.5 (t, J = 6 Hz), 106.9, 61.8, 56.4, 30.2 ppm; 13C{19F} NMR (100 MHz, CDCl3) δ 153.4, 152.4, 136.5, 134.5, 112.5, 106.9 (d, J = 158 Hz), 61.8 (q, J = 144 Hz), 56.4 (q, J = 144 Hz), 30.5 (t, J = 130 Hz); 19F{1H} NMR (376 MHz; CDCl3) δ (ppm) −125.9; HRMS (CI+, Orbitrap) m/z 337.1242 [M + H]+ (calcd for C18H19F2O4, 337.1246).

4,5-Difluoro-9,10-dihydrophenanthrene-2,3,6,7-tetraol (1c)

According to the procedure for tetrol 1b, using tetramethyl ether 6c (10 mg, 0.03 mmol) in CH2Cl2 (1 mL) and a solution of BBr3 in CH2Cl2 (1M, 0.2 mL, 0.2 mmol, 6 equiv) followed by quenching with MeOH and removal of the volatiles gave difluorotetrol 1c (8 mg, 96%) as a brown solid: IR (neat,) 3291 (br), 2922, cm–1; 1H NMR (400 MHz, CD3OD) δ (ppm) 8.45 (s, 4H), 6.53 (s, 2H), 2.52 (s, 4H); 19F{1H} NMR (376 MHz, CD3OD) δ −133.8 ppm; HRMS (CI–, Orbitrap) m/z 279.0473 [M – H]− (calcd for C14H9F2O4, 279.0463).

(E)-4,4′-(Ethene-1,2-diyl)bis(2-allyl-6-methoxyphenol) (3d)

According to a modified procedure for stilbene 3a, 5-allylvanillin 2d (2.88 g, 15 mmol, 1.0 equiv), Mg (720 mg, 30 mmol, 2.0 equiv), and TiCl4 (3.3 mL, 30 mmol, 2 equiv) were refluxed in THF for 16 h. After evaporation of the solvent and treatment with 2 M aqueous HCl (300 mL), the mixture was extracted with EtOAc (4 × 50 mL), and the combined organics were washed successively with 2 M aqueous HCl (100 mL), distilled H2O (2 × 1 00 mL), and brine (2 × 100 mL), dried over MgSO4, and evaporated to give diallylstilbene 3d (2.14 g, 6.1 mmol, 81%) as a red solid: IR (neat) 3410, 3075, 2933 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.91 (s, 2H), 6.89 (s, 2H), 6.86 (s, 2H), 6.03 (ddt, J = 16.7, 10.0, 6.5 Hz, 2H), 5.71 (s, 2H), 5.16–5.04 (m, 4H), 3.94 (s, 6H), 3.42 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ 146.7, 143.2, 136.7, 129.6, 126.6, 125.9, 121.2, 115.8, 106.1, 56.2, 34.0 ppm; HRMS (CI–, Orbitrap) m/z 353.1739 [M + H]+ (calcd for C22H25O4, 353.1747).

4,4′-(Ethane-1,2-diyl)bis(2-methoxy-6-propylphenol) (4d)

According to the procedure for diarylethane 4a, using stilbene 3d (705 mg, 2.00 mmol) and Pd/C (10 wt %, 100 mg) in THF (40 mL) gave dipropylethane 4d (707 mg, 1.98 mmol, 99%) as a wine red, sticky solid, which was used without further purification: IR (neat) 3540 (br), 2957, 2931, 2868, cm–1; 1H NMR (400 MHz, CDCl3) δ 6.58 (s, 2H), 6.51 (s, 2H), 5.52 (s, 2H), 3.84 (s, 6H), 2.78 (s, 4H), 2.58 (t, J = 7.6 Hz, 4H), 1.62 (sextet, J = 7.4 Hz, 4H), 0.96 (t, J = 7.4 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 146.1, 141.6, 132.9, 128.2, 122.3, 108.7, 56.1, 38.4, 32.0, 23.2, 14.2 ppm.

1,2-Bis(3,4-dimethoxy-5-propylphenyl)ethane (5d)

According to the procedure for tetramethyl ether 5c, using bis(methoxyphenol) 4d (600 mg, 1.67 mmol, 1 equiv), methyl iodide (1.1 mL, 17.7 mmol, 10.6 equiv), and potassium hydroxide (380 mg, 6.8 mmol, 4 equiv) in DMSO (50 mL), extracting with CH2Cl2, and purification by chromatography (EtOAc:PE 3:17) gave dipropyltetramethyl ether 5d (86 mg, 0.22 mmol, 13%) as white crystals: mp 62–64 °C; IR (neat) 2957, 2934, 2868 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.59 (s, 2H), 6.54 (s, 2H), 3.81 (s, 6H), 3.79 (s, 6H), 2.83 (s, 4H), 2.57 (t, J = 7.4 Hz, 4H), 1.59 (sextet, J = 7.4 Hz, 4H), 0.96 (t, J = 7.4 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 152.5, 145.5, 137.4, 136.2, 122.0, 110.6, 60.8, 55.8, 38.1, 32.0, 24.1, 14.3 ppm; HRMS (CI+, Orbitrap) m/z 387.2531 [M + H]+ (calcd for C24H35O4, 387.2530).

2,3,6,7-Tetramethoxy-4,5-dipropyl-9,10-dihydrophenanthrene (6d)

According to the procedure for dihydrophenanthrene 6b, using diarylethane 5d (80 mg, 0.21 mmol, 1 equiv) with [bis(trifluoroacetoxy)iodo]benzene (107 mg, 0.25 mmol, 1.2 equiv) and BF3·OEt2 (65 μL, 0.52 mmol, 2.5 equiv) in CH2Cl2 (10 mL), followed by chromatography (EtOAc:PE 3:17), gave dipropyldihydrophenanthrene 6d (52 mg, 0.14 mmol, 65%) as ivory needles: mp 118–121 °C; IR (neat) 2958, 2928, 2869, 2836 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.70 (s, 2H), 3.89 (s, 6H), 3.86 (s, 6H), 2.98–2.86 (m, 2H), 2.62–2.43 (m, 6H), 1.34 (m, 2H), 1.07 (m, 2H), 0.52 (t, J = 7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 150.9, 146.5, 136.3, 134.3, 128.6, 108.9, 61.1, 55.8, 31.9, 31.3, 24.2, 13.9; HRMS (CI+, Orbitrap) m/z 385.2380 [M + H]+ (calcd for C24H33O4, 385.2373).

4,5-Dipropyl-9,10-dihydrophenanthrene-2,3,6,7-tetraol (1d)

According to the procedure of tetrol 1b, using tetramethyl ether 6d (25 mg, 0.065 mmol) in CH2Cl2 (2 mL) and a solution of BBr3 in CH2Cl2 (1 M, 390 μL, 0.39 mmol, 6 equiv) followed by quenching with MeOH and removal of the volatiles gave dipropyltetrol 1c (19 mg, 0.058 mmol, 89%) as a brown powder: IR (neat) 3252 (br), 2957, 2928, 2868 cm–1; 1H NMR (400 MHz, CD3OD) δ 6.57 (s, 2H), 3.35 (s, 4H), 2.96–2.88 (m, 2H), 2.58–2.51 (m, 2H), 2.49–2.27 (m, 4H), 1.45–1.37 (m, 2H), 1.19–1.06 (m, 2H), 0.48 (t, J = 7.4 Hz, 6H) ppm; 13C NMR (100 MHz, CD3OD) δ 143.9, 142.8, 133.4, 129.0, 128.4, 112.3, 32.6, 31.6, 23.8, 13.7 ppm; HRMS (CI+, Orbitrap) m/z 329.1754 [M + H]+ (calcd for C20H25O4, 329.1747).

Acknowledgments

We thank the EPSRC (Grant No. EP/P030742/1 to D.C.B.) for financial support.

NMR spectra and X-ray diffraction and computational FAIR data are available at the Imperial College research data repository20 at DOI: 10.14469/hpc/10703.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jnatprod.2c00749.

  • General experimental; copies of 1H and 13C spectra for all new compounds; comparison of 1H NMR resonances for the dimethylene bridges of 4,5-disubstituted 9,10-phenanthrenes 6b–d and 1b–d in the region 3.00–2.00 ppm; analysis of the AA′XX′ “half-spectrum” multiplet at δ = 153.4 ppm for the fluorine-bearing carbons in the 13C NMR spectrum; X-ray crystal data for 4b, 5c, 6a–d, and 7c (CCDC 1947920–1947926); CSP-HPLC chromatograms for 6a–d (PDF)

The authors declare no competing financial interest.

Supplementary Material

np2c00749_si_001.pdf (4.1MB, pdf)

References

  1. a Wang B. G.; Gloer J. B.; Ji N.-Y.; Zhao J.-C. Halogenated Organic Molecules of Rhodomelaceae Origin: Chemistry and Biology. Chem. Rev. 2013, 113, 3632–3685. 10.1021/cr9002215. [DOI] [PubMed] [Google Scholar]; b Jesus A.; Correia-da-Silva M.; Afonso C.; Pinto M.; Cidade H. Isolation and Potential Biological Applications of Haloaryl Secondary Metabolites from Macroalgae. Mar. Drugs 2019, 17, 73. 10.3390/md17020073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barrett T. N.; Braddock D. C.; Monta A.; Webb M. R.; White A. J. P. Total Synthesis of the Marine Metabolite (±)-Polysiphenol via Highly Regioselective Intramolecular Oxidative Coupling. J. Nat. Prod. 2011, 74, 1980–1984. 10.1021/np200596q. [DOI] [PubMed] [Google Scholar]
  3. Aknin M.; Samb A.; Mirailles J.; Constantino V.; Fattorusso E.; Mangoni A. Polysiphenol, a New Brominated 9,10-Dihydrophenanthrene from the Senegalese Red Alga Polysyphonia Ferulacea. Tetrahedron Lett. 1992, 33, 555–558. 10.1016/S0040-4039(00)93994-7. [DOI] [Google Scholar]
  4. a Li K.; Li X.-M.; Ji N.-Y; Gloer J. B.; Wang B.-G. Urceolatin, a Structurally Unique Bromophenol from Polysiphonia Urceolata. Org. Lett. 2008, 10, 1429–1432. 10.1021/ol800230t. [DOI] [PubMed] [Google Scholar]; b Li K.; Li X.-M.; Ji N.-Y; Wang B.-G. Bromophenols from the Marine Red Alga Polysiphonia Urceolata with DPPH Radical Scavenging Activity. J. Nat. Prod. 2008, 71, 28–30. 10.1021/np070281p. [DOI] [PubMed] [Google Scholar]; c A formal total synthesis of (±)-polysiphenol has recently been reported:Kennedy S. H.; Dherange B. D.; Berger K.; Levin M. D. Nature 2021, 593, 223–227. 10.1038/s41586-021-03448-9. [DOI] [PubMed] [Google Scholar]
  5. Harvey B. G.; Guenthner A. J.; Meylemans H. A.; Haines S. R. L.; Lamison K. R.; Groshens T. J.; Cambrea L. R.; Davis M. C.; Lai W. W. Renewable Thermosetting Resins and Thermoplastics from Vanillin. Green Chem. 2015, 17, 1249–1258. 10.1039/C4GC01825G. [DOI] [Google Scholar]
  6. Shadakshari U.; Rele S.; Nayak S. K.; Chattopadhyay S. Low-Valent Titanium Mediated Synthesis of Hydroxystilbenoids: Some New Observations. Indian J. Chem., Sect. B 2004, 43, 1934–1938. 10.1002/chin.200451080. [DOI] [Google Scholar]
  7. Stilbene 3a has been reported as a side-product from the Clemmensen reduction of bromovanillin to the corresponding p-cresol.Ueda S.-i. Synthesis of 2, 7- bis(2- aminoethyl) - 4, 9- dimethoxydibenzo- p- dioxin. Yakugaku Zasshi 1962, 82, 714–18. 10.1071/CH9872137. [DOI] [Google Scholar]
  8. Cosmo R.; Sternhell S. Dehydrogenation of 4,5-Disubstitued 9,10-Dihydrophenanthrenes. Aust. J. Chem. 1987, 40, 2137–2142. 10.1071/CH9872137. [DOI] [Google Scholar]; Dehydrogenation of 4,5-dichloro-9,10-dihydrophenanthrene with DDQ in refluxing 1,2-dichlorobenzene for 90 h was reported to afford 4,5-dichlorophenanthrene in 55% yield: It proved possible to force the oxidation of dichloride 6b to its phenanthrene using DDQ in 1,2-dichlorobenzene with microwave heating (2.5 h, 60%). Our microwave modification therefore represents a significant improvement.
  9. An X-ray crystal structure of phenanthrene 7c (see Supporting Information) shows that the ring system is forced into approximate coplanarity, with F–F internuclear distance d = 2.38 Å and torsion angles of 16.3° (α), 9.4° (β), and 5.4° (γ). See Figure 2 for definitions of torsion angles.
  10. Sharma N.; Mohanakrishnan D.; Sharma U. K.; Kumar R.; Richa; Sinha A. K.; Sahal D. Design, Economical Synthesis and Antiplasmodial Evaluation of Vanillin Derived Allylated Chalcones and their Marked Synergism with Artemisinin against Chloroquine Resistant Strains of Plasmodium Falciparum. Eur. J. Med. Chem. 2014, 79, 350–368. 10.1016/j.ejmech.2014.03.079. [DOI] [PubMed] [Google Scholar]
  11. a Günther H. 1H-NMR Spectra of the AA′XX′ and AA′BB′ Type - Analysis and Classification. Angew. Chem., Int. Ed. Engl. 1972, 11, 861–874. 10.1002/anie.197208611. [DOI] [Google Scholar]; Compound 6c has a characteristic AA′XX′ “half-spectrum” multiplet at δ 153.4 for the fluorine-bearing carbons in its 13C NMR spectrum (see Supporting Information). The method of Günther allows the extraction of 1JFC = 188.2 Hz, 4JFC′ = 61.9 Hz, and 5JFF′ = 138.3 Hz (3JCC′ = 0): The 5JFF value observed here is directly comparable to those 5JFF values observed previously in 4,5-difluorophenathrenes:; b Mallory F. B.; Mallory C. W.; Ricker W. M. Nuclear Spin-Spin Coupling via Nonbonded Interactions. 4. F-F and H-F Coupling in Substituted Benzo[c]phenanthrenes. J. Org. Chem. 1985, 50, 457–461. 10.1021/jo00204a006. [DOI] [Google Scholar]; c Castillo N.; Matta C. F.; Boyd R. J. Fluorine-Fluorine Spin-Spin Coupling Constants in Aromatic Compounds: Correlations with the Delocalization Index and with the Internuclear Separation. J. Chem. Inf. Model. 2005, 45, 354–359. 10.1021/ci0497051. [DOI] [PubMed] [Google Scholar]; In addition, inspection of the two pairs of satellites around the singlet in the 19F NMR of 6c also allows for the extraction of 1JCF = 188.2 Hz and 4JCF = 64.0 Hz, matching the 13C NMR analysis.
  12. The molecular mechanics modeling (MM2 force field) in ref (3) gives torsion angles for polysiphenol 1a as α = 54°, β = 39°, and γ = 60°.
  13. The X-ray crystal structure for 4,5-dibromophenanthrene has recently been reported:; a Kim S. D. M.; Thamattoor D. M. Crystal structure of 4,5-di-bromo-phenanthrene. Acta Crystallogr. Sect. E Crystallogr. Commun. 2017, 73, 539–542. 10.1107/S2056989017003863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cosmo R.; Hambley T. W.; Sternhell S. Skeletal deformation in 4,5-disubstituted 9,10-dihydrophenanthrenes and 4,5-disubstituted phenanthrenes. J. Org. Chem. 1987, 52, 3119–3123. 10.1021/jo00390a029. [DOI] [Google Scholar]
  15. HPLC chromatograms for dibromide 6a, dichloride 6b, difluoride 6c, and dipropyl 6d on a chiral stationary phase (see Supporting Information) show that while fluoride 6c presents as a single peak, two peaks are each observed for the dibromide 6a, dichloride 6b, and dipropyl 6d, thereby confirming their room-temperature atropisomeric stability:Trapp O. Unified Equation for Access to Rate Constants of First-Order Reactions in Dynamic and On-Column Reaction Chromatography. Anal. Chem. 2006, 78, 189–198. 10.1021/ac051655r. [DOI] [PubMed] [Google Scholar]
  16. Chai J.-D.; Head-Gordon M. Long-range corrected hybrid density functionals with damped atom-atom dispersion corrections. Phys. Chem. Chem. Phys. 2008, 10, 6615–6620. 10.1039/b810189b. [DOI] [PubMed] [Google Scholar]
  17. Cossi M.; Rega N.; Scalmani G.; Barone V. Energies, structures, and electronic properties of molecules in solution with the C-PCM solvation model. J. Comput. Chem. 2003, 24, 669–681. 10.1002/jcc.10189. [DOI] [PubMed] [Google Scholar]
  18. Fukui K. The path of chemical-reactions - the IRC approach. Acc. Chem. Res. 1981, 14, 363–368. 10.1021/ar00072a001. [DOI] [Google Scholar]
  19. The atropisomeric stability of a series of 4,5-disubstituted-9,10-dihydrophenanthrenes has been previously assessed by VT-NMR methods:Cosmo R.; Sternhell S. Steric Effects. Inversion of 4,5-Disubstituted 9,l0-Dihydrophenanthrenes. Aust. J. Chem. 1987, 40, 35–47. 10.1071/CH9870035. [DOI] [Google Scholar]
  20. For all managed computational research data, including input and output files, and for primary NMR and X-Ray data see:Braddock D. C.; Duran-Corbera A.; Nilfouroushan M.; Yang Z.; He T.; Santhakumar G.; Bahou K. A.; Rzepa H. S.; White A. J. P. Imperial College Research Data Repository 2022, 10.14469/hpc/10703. [DOI] [PMC free article] [PubMed] [Google Scholar]

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Supplementary Materials

np2c00749_si_001.pdf (4.1MB, pdf)

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